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Mechanisms of Substrate Selection by the Signal Recognition Particle

Citation

Ariosa, Aileen Renia (2014) Mechanisms of Substrate Selection by the Signal Recognition Particle. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/AEDK-0925. http://resolver.caltech.edu/CaltechTHESIS:05302014-103528106

Abstract

The signal recognition particle (SRP) targets membrane and secretory proteins to their correct cellular destination with remarkably high fidelity. Previous studies have shown that multiple checkpoints exist within this targeting pathway that allows ‘correct cargo’ to be quickly and efficiently targeted and for ‘incorrect cargo’ to be promptly rejected. In this work, we delved further into understanding the mechanisms of how substrates are selected or discarded by the SRP. First, we discovered the role of the SRP fingerloop and how it activates the SRP and SRP receptor (SR) GTPases to target and unload cargo in response to signal sequence binding. Second, we learned how an ‘avoidance signal’ found in the bacterial autotransporter, EspP, allows this protein to escape the SRP pathway by causing the SRP and SR to form a ‘distorted’ complex that is inefficient in delivering the cargo to the membrane. Lastly, we determined how Trigger Factor, a co-translational chaperone, helps SRP discriminate against ‘incorrect cargo’ at three distinct stages: SRP binding to RNC; targeting of RNC to the membrane via SRP-FtsY assembly; and stronger antagonism of SRP targeting of ribosomes bearing nascent polypeptides that exceed a critical length. Overall, results delineate the rich underlying mechanisms by which SRP recognizes its substrates, which in turn activates the targeting pathway and provides a conceptual foundation to understand how timely and accurate selection of substrates is achieved by this protein targeting machinery.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Signal Recognition Particle, Trigger Factor
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Biochemistry and Molecular Biophysics
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Shan, Shu-ou
Thesis Committee:
  • Rees, Douglas C. (chair)
  • Miller, Thomas F.
  • Parker, Carl Stevens
  • Shan, Shu-ou
Defense Date:24 May 2014
Funders:
Funding AgencyGrant Number
NIHGM095294
Record Number:CaltechTHESIS:05302014-103528106
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05302014-103528106
DOI:10.7907/AEDK-0925
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8441
Collection:CaltechTHESIS
Deposited By: Aileen Ariosa
Deposited On:31 May 2014 00:07
Last Modified:11 Apr 2019 17:50

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